The PI together with a number of collaborators, has shown that two members of the large Eph family of neural specific tyrosine kinases are used to control axon path finding in the brain, vestibular system and spinal cord. These findings, together with work of other investigators on these molecules, has raised interest in the Eph family of receptors and their membrane-anchored ligands. Ongoing studies of EphB2 and EphB3 indicate that these two receptors have unique functions and in addition share overlapping or redundant functions probably due to the fact that both of these receptors bind to and are activate by the same three transmembrane ligands, ephrin-B1, -B2 and -B3. The proposal describes experiments aimed at further characterizing the in vivo functions of these receptors and ligands. It is anticipated that these studies will help us understand how axons respond to the novel bi-directional tyrosine kinase signals transduced by these molecules. Three specific aims are proposed: (1) To continue analysis of EphB2 and EphB3 receptor function in the mouse. (2) To identify genetic modifiers that interact with EphB2 and EphB3 mutations and (3 To characterize the biological functions and signaling properties of the ephrin-B1 ligand. A developmental genetic analysis of these highly conserved cell axon signaling molecules is of critical importance to our future understanding of the biochemical mechanisms that control neural pathfinding. This knowledge may help lead to the discovery of new therapies useful in the treatment of neural damage and disease.